Biology subjects

Goetzler, E.

Publications and source records attributed to Goetzler, E..

3 recordsLinked to original sources

bioRxiv2026

Developmental rewiring of EHMT1 function during human cortical neurogenesis

Ubiquitously expressed chromatin regulators orchestrate cell-type-specific gene expression programs, yet how they acquire distinct regulatory functions during development remains fundamentally unresolved. Using temporally controlled protein depletion during human cortical neurogenesis in vitro, we show that the autism-associated histone methyltransferase EHMT1 is developmentally repurposed from epiblast to cortical neurons. Broadly expressed zinc finger proteins recruit EHMT1 to distinct cis-regulatory elements within changing chromatin landscapes associated with lineage-specific transcription factor activity, with extensive remodeling of EHMT1 enhancer occupancy during neural induction dependent on ZNF462. This genomic rewiring is accompanied by a fundamental shift from restraining premature developmental gene expression in pluripotent cells to supporting neuronal programs, with distinct transcriptional consequences of EHMT1 loss across neural progenitors and excitatory and inhibitory neuronal subtypes. Timed depletion and recovery experiments identify the neural progenitor stage as the onset of a developmental period during which EHMT1 is required for faithful neuronal maturation. Remarkably, EHMT1 can re-engage stage-specific targets after prolonged deficiency, allowing extensive transcriptional recovery with only limited molecular scarring. These findings reveal how ubiquitous epigenetic machinery acquires developmental specificity while demonstrating the resilience of developmental gene regulatory programs to prolonged disruption, with implications for neurodevelopmental disorders.

developmental biology↗

bioRxiv2025

The bacterial chaperone CsgC inhibits functional amyloid CsgA formation by promoting the intrinsically disordered pre-nuclear state

E. coli assembles a functional amyloid called curli during biofilm formation. The major curlin subunit is the CsgA protein, which adopts a beta-sheet rich fold upon fibrillization. The chaperone-like protein CsgC inhibits CsgA amyloid formation. CsgA undergoes a 3-stage aggregation process: an initial lag phase where beta-rich nuclei form, an exponential elongation phase, and a plateau phase. It is currently not known if CsgC inhibits amyloid formation by inhibiting formation of a pre-fibril nucleus, or if CsgC inhibits a later stage of amyloid formation by blocking monomer addition. Here, CsgC homologs from C. youngae, C. davisae, and H. alvei were purified and characterized for their ability to interrogate CsgA amyloid formation. Each of the CsgC homologs prolonged the lag phase of E. coli CsgA amyloid formation similar to E. coli CsgC. Additionally, we found E. coli CsgC interacted transiently and weakly with a monomeric, pre-nucleus species of CsgA which delayed amyloid formation. A transient CsgC-CsgA heterodimer was observed using ion mobility-mass spectrometry. When CsgC was added to actively polymerizing CsgA, exponential growth commonly associated with nucleation-dependent amyloid formation was lost. Adding preformed CsgA seeds did not rescue exponential growth, indicating that CsgC also has inhibitory activity during fibril elongation. Indeed, CsgC interacted strongly with CsgA fibers, suggesting the interaction between CsgC and CsgA fibers can slow new fiber growth. CsgC displays unique inhibitory activity at multiple stages of amyloid formation. CsgC acts as an energy-independent chaperone that transiently interacts with prefibrillar CsgA and an amyloid fiber.

biochemistry↗

bioRxiv2024

Transcriptional remodeling by OTX2 directs specification and patterning of mammalian definitive endoderm

O_LIMouse and human pluripotent cells with multipurpose degron alleles establish versatile platforms to dissect cell type-specific functions of the pleiotropic transcription factor OTX2 C_LIO_LIOTX2 controls molecular programs required for anterior-posterior patterning of the developing gut C_LIO_LIOTX2 establishes and maintains chromatin accessibility at distinct distal gene regulatory elements in definitive endoderm C_LIO_LIOTX2 functions as a patterning factor across different germ layers and species C_LI The molecular mechanisms that drive essential developmental patterning events in the mammalian embryo remain poorly understood. To generate a conceptual framework for gene regulatory processes during germ layer specification, we analyzed transcription factor (TF) expression kinetics around gastrulation and during in vitro differentiation. This approach identified Otx2 as a candidate regulator of definitive endoderm (DE), the precursor of all gut-derived tissues. Analysis of multipurpose degron alleles in gastruloid and directed differentiation models revealed that loss of OTX2 before or after DE specification alters the expression of core components and targets of specific cellular signaling pathways, perturbs adhesion and migration programs as well as de-represses regulators of other lineages, resulting in impaired foregut specification. Key targets of OTX2 are conserved in human DE. Mechanistically, OTX2 is required to establish chromatin accessibility at candidate enhancers, which regulate genes critical to establishing an anterior cell identity in the developing gut. Our results provide a working model for the progressive establishment of spatiotemporal cell identity by developmental TFs across germ layers and species, which may facilitate the generation of gut cell types for regenerative medicine applications.

developmental biology↗